Misregulation of insulin and IGF signaling (IIS) is associated with metabolic diseases such as diabetes and can increase cancer incidence. Insulin signaling is modulated by nutritional inputs, and IIS controls both cell growth and metabolism. Research in genetic model organisms has revealed that, in addition to these metabolic and growth control functions, IIS can increase the sensitivity to oxidative stress and accelerate senescence. Conversely, a decrease in IIS activity can promote environmental stress tolerance and confer longevity to worms, flies, and mice. It is thus plausible that both metabolic and stress signals can modulate IIS pathway responses. Since such mechanisms would directly link processes controlling growth and senescence, they would be of pivotal biomedical interest. The applicants have found in preliminary studies on Drosophila melanogaster that stress and metabolic signaling - transduced via the Jun-N-terminal Kinase (JNK) and the IIS pathway, respectively - converge on Foxo, a transcription factor that has been shown to promote the stress resistance and longevity of multi cellular organisms. This proposal describes experiments that will test the hypothesis that JNK signaling activates Foxo to repress IIS-mediated growth and promote repair mechanisms in response to stress, thus increasing stress tolerance and longevity. A validation of this model and a detailed analysis of the underlying regulatory interactions between JNK and IIS signaling, is of high priority. This work will provide insight into possible molecular causes of aberrant insulin signaling and offer potential avenues for therapeutic intervention targeted towards metabolic dysfunctions such as insulin resistance. The proposal is organized along three specific aims combining genetic and biochemical approaches in the Drosophila system: To elucidate the molecular mechanism by which JNK signaling activates Foxo and antagonizes IIS. To examine how the interplay between JNK and IIS signaling regulates organism growth and senescence. To test the hypothesis that the life span regulator Sir2 cooperates with JNK in the activation of Foxo and the mediation of its biological effects.